Fig. 3

Genome first approach at FTO GWAS locus. Claussnitzer et al [16] combined genomics, epigenomics, transcriptomics, and phylogenetic analysis to identify the functional element, the causative SNP, and the downstream genes mediating the genetic effect at the FTO locus in obesity. Circles represent genes in the locus and yellow circles represent genes implicated by the respective omics data. a Genomics: the FTO locus, containing several genes (circles), harbors the most significant obesity-associated haplotype in humans. SNPs that are in linkage disequilibrium with the risk allele are color coded—blue represents the non-risk (normal) haplotype and red the risk haplotype. b Epigenomics: publically available epigenomic maps and functional assays were used to narrow down the original associated region to 10 kb containing an adipose-specific enhancer. Chromatin capturing (Hi-C) was used to identify genes interacting with this enhancer. c Transcriptomics: this technique was used to identify which of the candidate genes are differentially expressed between the risk and normal haplotypes, identifying IRX3 and IRX5 as the likely downstream targets. In addition, conservation analysis suggested that rs1421085 (SNP that disrupts an ARID5B binding motif) is the causative SNP at the FTO locus. CRISPR-Cas9 editing of rs1421085 from background (TT) to risk allele (CC) was sufficient to explain the observed differences in expression of IRX3 and IRX5. d Functional mechanism: correlation and enrichment analysis were then used to identify potentially altered pathways that were then confirmed by in vitro and in vivo studies